This application extends ongoing work in the regulation of ACTH secretion through investigation of the interaction of female gonadal hormones and the hypothalamic-pituitary-adrenal (HPA) axis. It has already been established in many species, including humans, that alterations in plasma ACTH and corticosteroid levels occur in association with changes in both estrogen (E) and progesterone (P). However much of this work is now old and, especially in the rat, has yielded inconsistent results. Furthermore, studies are scarce regarding the precise temporal relationship of gonadal hormone secretion and are scarce regarding the precise temporal relationship of gonadal hormone secretion and HPA activity in response to stress. And yet these interactions are of critical importance in better understanding the mechanisms underlying stress-induced disorders in women (e.g. affective disorders which is 2-3 times more prevalent in women) and the mood changes frequently associated with the menstrual cycle (e.g. premenstrual syndrome). Preliminary data in this laboratory obtained from adult long-term ovariectomized female rats show elevated basal levels of plasma ACTH and corticosterone (CS) and enhanced plasma ACTH response to footshock stress compared to randomly cycling intact females. These exaggerated responses returned toward intact values with E replacement. Hence the summary hypothesis is that changes in gonadal hormone levels, as occur during the estrus cycle and following gonadectomy, alter the regulation of ACTH and CS secretion and also the response of these hormones to stress. To explore this hypothesis we will determine: 1) Basal plasma ACTH and CS levels and responses to a standardized footshock stress in intact female rats at different phases of their estrous and diurnal cycle. 2) The time-course of the postgonadectomy changes in the circadian rhythms of basal plasma ACTH and CS concentrations and their responses to footshock stress. 3) The effect of cyclic replacement of E and/or P on the basal and stress-induced changes in the HPA activity of ovariectomized rat. 4) The stimulus-secretion characteristics of hypothalamic CRF, AVP and anterior pituitary ACTH release in vitro, using tissues obtained from rats at different stages of their estrous cycle or after ovariectomy.